The present invention relates to the use of novel organoselenium compounds as pro-oxidizing agents, their methods of preparation and pharmaceutical compositions and application thereof.
The reactive oxygen entities (ROEs), such as, for example, the superoxide anion (O2xe2x88x92) and hydrogen peroxide (H2O2), coming from metabolism of oxygen, generated within the cell are under the control of the antioxidizing protection system. This system is composed in particular of macromolecules with enzymatic activity such as superoxide dismutases (SOD), catalase and glutathione peroxidases, as well as small molecules with high reducing potential such as, for example, glutathione, vitamin E, vitamin C and lipoic acid. This antioxidizing system plays a central role in the prevention of  less than  less than oxidative stress greater than  greater than  and its deleterious consequences (1).
In normal physiological situations, an equilibrium between the production and the decomposition of these reactive oxygen entities (ROEs) already exists in the cell. If this fragile equilibrium becomes durably disrupted under the influence of a physical stimulus (UV, ionizing radiation, . . . ), or an internal chemical stimulus (cytokines), or an external chemical stimulus (xenobiotics, cigarettes, . . . ) the production of these ROEs surpassing the antioxidizing protection system, the cellular structures (membranes, mitochondria, DNA, . . . ) are destroyed. This phenomenon being able to lead irreversibly to cellular death if this imbalance attains a critical threshold. This general physiopathological mechanism has been proposed in a large number of diseases such as inflammatory diseases (see Ann. Rev. Physiol.; 1986, 48, 681-692 and Ann. Rev. Resp. Dis. 1989, 139, 1553-1564), cardiovascular diseases (see Free Radic. Biol. Med.; 1994, 16, 35-41), the genesis of certain cancers (see Science; 1983, 221, 1256-1264 and Ann. Rev. Pharmacol. Toxicol.; 1985, 25, 509-528 as well as Free Radic. Biol. Med.; 1994, 16, 99-109) as well as for the phenomenon of ageing.
The controlled generation of these ROEs has proved to be formidable weapon for the destruction of certain target cells such as tumor cells. The pharmacological concept consisting in the use of cytotoxic drugs which generate reactive oxygen entities was implicitly bound to the mode of action of anti-cancer drugs such as, for example, bleomycin (see  less than  less than Bleomycin: chemical, biochemical and biological aspects greater than  greater than ; Hecht S. M. ed.; (1979); Springer Verlag, N.Y.; 24) whose target is DNA, anthracyclines (daunorubicin, daunomycin, . . . ) (see P. N. A. S.; 1986, 83, 4514 and Biochem.; 1987, 26, 3776), mitomycin C and its analogues (Int. J. Radiat. Oncol. Biol. Phys.; 1979, 5, 851), nitroimidazoles (misonidazole, pimonidazole, . . . ) (see Int. J. Radiat. Oncol. Biol. Phys.; 1992, 22, 643 and 649) amongst others.
Furthermore, it has been demonstrated that the toxicity of organoselenium compounds of the selenol and/or diselenide type is in a large part due to the catalytic reduction of oxygen giving superoxide and hydrogen peroxide (see Arch. Biochem. Biophys.; 1992, 296, 328-336).
On the other hand, various benzisoselenazolines and benzisoselenazines were described by the Applicant in the prior U.S. Pat. No. 2,718,441 which possess a therapeutic activity as antioxidizing and anti-inflammatory agents. The substituents on the benzene ring can occupy any of the positions and no compound described possesses an aromatic substituent in a position ortho to the selenium, with the exception of one sole compound which possesses a nitro substitution in ortho combined with a dimethyl substitution in benzylic position.
One of the aims of the present invention is to conceive organoselenium compounds possessing a catalytic pro-oxidizing activity, i.e. an activity generating reactive oxygen entities which can destroy a target cell, in particular a pathogenic cell, such as a tumor cell.
These compounds must be able to penetrate the interior of the target tissues or cells, they must be water-soluble at active concentrations and must efficiently reduce oxygen to give toxic by-products.
These aims are attained by this invention which consists in the design of novel organoselenium derivatives whose pro-oxidizing and cytotoxic activities as well as their methods of preparation are described.
It is completely surprising, in the framework of the present invention, that the organoselenium derivatives possess a pro-oxidizing activity, given that the organoselenium compounds described in the prior application of the applicant, FR-A-94 04107, which had been shown to possess an anti-oxidizing activity and had been tested as such. From this fact, although it had been described that the radicals R1 and R2 could stand for xe2x80x94NO2, in general, their position on the benzene ring was not specified and only one example described the synthesis of a derivative bearing a nitro group in the position ortho to the selenium on the benzene ring. This compound was claimed as a novel compound, but was inactive as an anti-oxidizing agent.
The aim of the present invention is:
1) to solve the novel technical problem consisting in providing novel organoselenium derivatives possessing excellent pro-oxidizing and cytotoxic activities, which can thus constitute a valuable active ingredient in the framework of pharmaceutical compositions;
2) to solve the novel technical problem, set forth above, with a solution which also provides a method for the preparation of these compounds which is relatively easy to carry out;
These aspects of the technical problem- described above are simultaneously solved by the present invention by a simple solution, with a preparation method which is relatively easy to carry out and which gives good yields.
In a first aspect, the present invention provides novel organoselenium compounds of the following general formula(I):

wherein:
R1 is selected from a group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R2 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R3 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R4 is selected from the group consisting of: xe2x80x94NO2; xe2x80x94NO; xe2x80x94CN; xe2x80x94COOR9; xe2x80x94SO3R9; xe2x80x94CONR9R11 and xe2x80x94SO2NR9R11;
R5 is selected from the group consisting of: hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; xe2x80x94(CH2)pVect; xe2x80x94N+R113Yxe2x88x92; xe2x80x94SO3xe2x88x92Z+ and xe2x80x94CO2xe2x88x92Z+;
X is selected from the group consisting of: (CR6R7)n; and CO;
R6 is selected from the group consisting of: hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R7 is selected from the group consisting of: hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R8 is selected from the group consisting of: C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from Cl-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; heteroaryl; heteroaryl substituted by one or more identical or different groups selected from: C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; and xe2x80x94(CH2)pVect;
R9 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; and xe2x80x94(CH2)pVect;
R10 is selected from the group consisting of: hydrogen; xe2x80x94N+R113Yxe2x88x92; xe2x80x94SO3xe2x88x92Z+ and xe2x80x94CO2xe2x88x92Z+;
R11 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl;
Vect=
W represents either a simple linkage with xe2x80x94(CH2)pxe2x80x94, or a heteroatom such as O, S or N, bound to xe2x80x94(CH2)pxe2x80x94;
Yxe2x88x92 represents the anion of a pharmaceutically acceptable acid;
Z+ represents the cation of a pharmaceutically acceptable base;
n=0, 1;
m=0, 1;
p=2 to 10;
and their salts of pharmaceutically acceptable acids or bases;
with the proviso that there can not be more than one Vect substituent within each molecule of the general formula I.
With the further proviso that:
When R4 is xe2x80x94NO2, then at least one of R2 and R3 is other than methyl.
In the framework of the description and the claims:
the tenn  less than  less than lower alkyl group greater than  greater than  or  less than  less than C1-C6 alkyl group greater than  greater than  means linear or branched groups containing 1 to 6 carbon atoms;
the term  less than  less than substituted greater than  greater than , as applied to the aryl or aralkyl groups, means that these are substituted in the aromatic portion by one or more identical or different groups selected from: C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H; xe2x80x94CO2xe2x80x94(C1-C6)alkyl; or by one or more hydrogen atoms;
when R4 represents xe2x80x94COOH, xe2x80x94SO3H, the invention also covers the addition salts of a pharmaceutically acceptable base.
Amongst the pharmaceutically acceptable acids, cited in a non-limiting way, are: hydrochloric, hydrobromic, hydroiodic, sulfuric, tartaric, methanesulfonic, trifluoromethanesulfonic acid, etc . . .
Amongst the pharmaceutically acceptable bases, cited in a non-limiting way, are: sodium and potassium hydroxides, alkali metal or alkaline-earth metal carbonates or organic bases such as triethylamine or arginine, etc . . .
In a second aspect, the present invention relates to the use of organoselenium compounds of the following general formula (IA):

wherein:
R1 is selected from a group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2))pR10; and xe2x80x94(CH2)pVect;
R2 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R3 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R4is selected from the group consisting of: xe2x80x94NO2; xe2x80x94NO; xe2x80x94CN; xe2x80x94COOR9; xe2x80x94SO3R9; xe2x80x94CONR9R11 and xe2x80x94SO2NR9R11;
R5 is selected from the group consisting of: hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; xe2x80x94(CH2)pVect; xe2x80x94N+R113Yxe2x88x92; xe2x80x94SO3xe2x88x92Z+ and xe2x80x94CO2xe2x88x92X+;
X is selected from the group consisting of: (CR6R7)n; and CO;
R6 is selected from the group consisting of: hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R7 is selected from the group consisting of: hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R8 is selected from the group consisting of: C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; heteroaryl; heteroaryl substituted by one or more identical or different groups selected from: C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; and xe2x80x94(CH2)pVect;
R9 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; and xe2x80x94(CH2)pVect;
R10 is selected from the group consisting of: hydrogen; xe2x80x94N+R113Yxe2x88x92; xe2x80x94SO3xe2x88x92Z+ and xe2x80x94CO2xe2x88x92Z+;
R11 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl;
Vect=
W represents either a simple linkage with xe2x80x94(CH2)pxe2x80x94, or a heteroatom such as O, S or N, bound to xe2x80x94(CH2)pxe2x80x94,
Yxe2x88x92 represents the anion of a pharmaceutically acceptable acid;
Z+ represents the cation of a pharmaceutically acceptable base;
n=0, 1;
m=0, 1;
p=2 to 10;
and their salts of pharmaceutically acceptable acids or bases;
with the proviso that there can not be more than one Vect substituent within each molecule of the general formula IA;
as a pro-oxidizing agent.
The invention also covers the methods of therapeutic treatment corresponding to this use, as is well understandable for a person skilled in the art.
In an advantageous embodiment, the present invention relates to the use of the above-mentioned compounds of general formula IA for the manufacture of a pharmaceutical composition with pro-oxidizing activity, in particular in the treatment of cancers in which an intracellular overproduction of cytotoxic reactive oxygen entities contributes to functional alterations in the corresponding tumor cells.
In these cancerous pathologies, the active ingredient can be administered via the oral, rectal or topical route, or even by intramuscular or intravenous injection.
In another advantageous embodiment, the organoselenium derivative of the above-mentioned general formula (IA) is present in an amount in the range 0.01% to 5% by weight with respect to the total weight of the final composition, preferably in the range 0.1% to 1% by weight.
In another advantageous embodiment, the present invention relates to the use of the composition in the form of unit dose which may comprise 1 mg to 500 mg of the organoselenium derivative of the above-mentioned general formula (IA), optionally in a pharmaceutically acceptable excipient, vehicle or support.
In a third aspect, the present invention also provides a pharmaceutical composition, in particular with pro-oxidizing activity, characterized in that it comprises, as active ingredient, at least one organoselenium derivative of the following general formula (IA):

wherein:
R1 is selected from a group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R2 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R3 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONH2; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R4 is selected from the group consisting of: xe2x80x94NO2; xe2x80x94NO; xe2x80x94CN; xe2x80x94COOR9; xe2x80x94SO3R9; xe2x80x94CONR9R11 and xe2x80x94SO2NR9R11;
R5 is selected from the group consisting of hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; xe2x80x94(CH2)pVect; xe2x80x94N+R113Yxe2x88x92; xe2x80x94SO3xe2x88x92Z+ and xe2x80x94CO2xe2x88x92Z+;
X is selected from the group consisting of: (CR6R7)n; and CO;
R6 is selected from the group consisting of: hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R7 is selected from the group consisting of: hydrogen; C1-C6 alkyl; xe2x80x94COR8; xe2x80x94COOR8; xe2x80x94CONR8R9; xe2x80x94(CH2)pR10; and xe2x80x94(CH2)pVect;
R8 is selected from the group consisting of: C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94COxe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; heteroaryl; heteroaryl substituted by one or more identical or different groups selected from: C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; and xe2x80x94(CH2)pVect;
R9 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; and xe2x80x94(CH2)pVect;
R10 is selected from the group consisting of: hydrogen; xe2x80x94N+R113Yxe2x88x92; xe2x80x94SO3xe2x88x92Z+ and xe2x80x94CO2xe2x88x92Z+;
R11 is selected from the group consisting of: hydrogen; C1-C6 alkyl; ar(C1-C6)alkyl; ar(C1-C6)alkyl substituted on aryl by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl; aryl; aryl sustituted by one or more identical or different groups selected from C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, hydroxyl, nitro, amino, C1-C6 alkylamino, di(C1-C6-alkyl)amino, sulfonyl, sulfonamide, sulfo(C1-C6-alkyl), xe2x80x94CO2H, and xe2x80x94CO2xe2x80x94(C1-C6)alkyl;
Vect=
W represents either a simple linkage with xe2x80x94(CH2)pxe2x80x94, or a heteroatom such as O, S or N, bound to xe2x80x94(CH2)pxe2x80x94;
Yxe2x88x92 represents the anion of a pharmaceutically acceptable acid;
Z+ represents the cation of a pharmaceutically acceptable base;
n=0, 1;
m=0, 1;
p=2 to 10;
and their salts of pharmaceutically acceptable acids or bases;
with the proviso that there can not be more than one Vect substituent within each molecule of the general formula IA.
In a fourth aspect, the invention covers a method of preparation of an organoselenium compound of the above-mentioned general formula IA, characterized in that it comprises the following essential steps (see Scheme 1):
a) preparing or using a correctly substituted 3-nitro-2-halophenylacetonitrile derivative,
then depending on the series considered:
either
b1) hydrolyzing the nitrite derivative to an amide derivative,
c1) transforming this amide derivative into an amine derivative by a transposition reaction using usual methods,
d1) N-acylating this amine derivative using usual procedures;
e1) reacting the latter with a nucleophilic selenium derivative, which may be generated in situ, in the presence of a copper salt, in a polar organic solvent, in order to produce the corresponding benzisoselenazoline derivative,
f1) hydrolysing the heterocyclic derivative thus obtained, if necessary, to the corresponding amine in order to be N-alkylated if necessary using usual procedures;
g1) finally, oxidizing the derivative thus obtained if necessary using usual procedures;
or
b2) reducing the nitrite derivative to an amine derivative with the aid of a reducing agent such as, for example, borane in an ethereal solvent such as, for example, tetrahydrofuran,
c2) N-acylating the amine compound using usual procedures;
d2) reacting the amine compound with a nucleophilic selenium derivative, if necessary generated in situ, in the presence of a copper salt, in a polar organic solvent, in order to produce the corresponding benzisoselenazine derivative,
e2) hydrolyzing the heterocyclic derivative thus obtained if necessary to the corresponding amine in order to be N-alkylated, if necessary, using usual procedures;
f2) finally, oxidizing the derivative thus obtained if necessary using usual procedures;
or
b3) mono- or di-alkylating the nitrite derivative to give an amine derivative,
c3) N-acylating this amine compound using usual procedures;
d3) reacting this amine compound with a nucleophilic selenium derivative, if necessary generated in situ, in the presence of a copper salt, in a polar organic solvent, in order to produce the corresponding benzisoselenazine derivative,
e3) hydrolyzing the heterocyclic derivative thus obtained if necessary to the corresponding amine in order to be N-alkylated if necessary, using usual procedures;
f3) finally, oxidizing the derivative thus obtained if necessary, using usual procedures;
It should be noted that in the framework of the invention, the N-acylation of the amine compound is carried out before proceeding with the reaction with the nucleophilic selenium derivative, since this improves the yield of this synthesis in an unexpected manner.
Another implementation of this procedure is characterized in that the nucleophilic selenium compound is preferably a selenocyanate salt such as, for example, potassium selenocyanate which can be:
either generated in situ from elemental selenium (Seo) and a cyanide salt such as, for example, potassium cyanide,
or added to the reaction medium as it is.
Yet another particular implementation of the method is characterized in that the copper salt can be a cuprous salt (Cul), such as, for example, cuprous iodide.
Another implementation of this method is characterized in that the polar organic solvent is preferably dimethylformamide.
Another implementation of this method is characterized in that the oxidizing agent which is optionally used can be a peracid, such as meta-chloroperbenzoic acid, or hydrogen peroxide.
Other aims, characteristics and advantages of the invention will become clear from the following description which is made with reference to non-limiting examples which are given simply by way of illustration and in no way limit the scope of the invention. In the examples, all the percentages are given as percentages by weight unless stated otherwise. Furthermore, in all the examples, the temperature is expressed in degrees Celsius and the reaction takes place at atmospheric pressure and at room temperature unless stated otherwise.